RNA participates widely in gene expression and regulation at the levels of transcription, mRNA maturation, and translation in cells (Fire et al., 1998; Mello & Conte, 2004; Ma et al., 2005; Macrae et al., 2006; Sudarsan et al., 2006; Cheah et al., 2007; Nagano et al., 2008; Guo et al., 2010; Heo & Sung, 2011; Wiedenheft et al., 2012). These observations are consistent with the RNA world hypothesis (Gesteland et al., 2006) and the preservation of functions of RNAs, such as ribosomal RNAs and the peptidyl transferase ribozyme (Nissen et al., 2000; Harms et al., 2001; Agmon, 2009; Fox et al., 2012). However, it is unknown whether RNA can directly influence DNA polymerase and synthesis both in vitro and in vivo, though the DNA synthesis in both prokaryotes and eukaryotes is highly regulated (Nishitani & Lygerou, 2002; Paulsson & Chattoraj, 2006).
Since dNTPs are constantly present in cells, regulation of the availability and level of the DNA precursors (dNTPs) is considered to be a major strategy in controlling DNA polymerization (Ji & Mathews, 1991; Chabes & Stillman, 2007; Rampazzo et al., 2010; Gon et al., 2011; Niida et al., 2011). Improper quantity and imbalance of dNTPs may hamper DNA polymerization and fidelity, leading to mutation, genomic instability, and even cell death (Elledge & Davis, 1990; Mathews & Ji, 1992; Zhao et al., 1998; Mathews, 2006). Clearly, tight control of the dNTP level helps regulating DNA synthesis in cells.
It is an object of the present invention to provide methods and compositions by which DNA synthesis is inhibited by RNA. It is also an object of the present invention to provide methods and compositions that inhibit cells and cell growth by inhibiting DNA synthesis. It is also an object of the present invention to provide methods and compositions for treating cancer by inhibiting cancer cells and cancer cell growth by inhibiting DNA synthesis.